Regulatory mechanisms that modulate signalling by G-protein-coupled receptors.
Regulatory mechanisms that modulate signalling by G-protein-coupled receptors.
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DOI：
10.1042/bj3220001
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发表时间：
1997-02
期刊：
影响因子：
--
通讯作者：
S. Böhm;E. Grady;N. Bunnett
中科院分区：
文献类型：
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作者：
S. Böhm;E. Grady;N. Bunnett
功能多样的大量 G 蛋白偶联受体包括许多不同信号分子的受体，包括肽和非肽激素以及神经递质、趋化因子、前列腺素和蛋白酶。它们的主要功能是通过与异源三聚体 G 蛋白相互作用将细胞外环境的信息传递到细胞内部，从而参与许多方面的调节。细胞对这些受体激动剂的反应通常会迅速减弱。信号衰减的机制包括从细胞外液中去除激动剂、受体脱敏、内吞作用和下调。激动剂通过稀释、转运蛋白吸收和酶降解而被去除。受体脱敏是通过 G 蛋白受体激酶和第二信使激酶的受体磷酸化、磷酸化受体与抑制蛋白的相互作用以及受体与 G 蛋白解偶联来介导的。激动剂诱导的受体内吞作用还通过消耗细胞表面的高亲和力受体而有助于脱敏，并且内化受体的再循环有助于细胞反应的重新敏化。受体下调是一种脱敏形式，发生在细胞持续、长期暴露于受体激动剂的过程中。下调可能发生在药物耐受性的发展过程中，其特征是细胞受体含量的耗尽，并且可能是由受体降解和合成速率的改变介导的。这些调节机制很重要，因为它们控制细胞对激动剂作出反应的能力。对调节信号传导机制的更深入了解可能会导致新疗法的开发，并可能有助于解释药物耐受机制。
The large and functionally diverse group of G-protein-coupled receptors includes receptors for many different signalling molecules, including peptide and non-peptide hormones and neuro-transmitters, chemokines, prostanoids and proteinases. Their principal function is to transmit information about the extracellular environment to the interior of the cell by interacting with the heterotrimeric G-proteins, and they thereby participate in many aspects of regulation. Cellular responses to agonists of these receptors are usually rapidly attenuated. Mechanisms of signal attenuation include removal of agonists from the extracellular fluid, receptor desensitization, endocytosis and down-regulation. Agonists are removed by dilution, uptake by transporters and enzymic degradation. Receptor desensitization is mediated by receptor phosphorylation by G-protein receptor kinases and second-messenger kinases, interaction of phosphorylated receptors with arrestins and receptor uncoupling from G-proteins. Agonist-induced receptor endocytosis also contributes to desensitization by depleting the cell surface of high-affinity receptors, and recycling of internalized receptors contributes to resensitization of cellular responses. Receptor down-regulation is a form of desensitization that occurs during continuous, long-term exposure of cells to receptor agonists. Down-regulation, which may occur during the development of drug tolerance, is characterized by depletion of the cellular receptor content, and is probably mediated by alterations in the rates of receptor degradation and synthesis. These regulatory mechanisms are important, as they govern the ability of cells to respond to agonists. A greater understanding of the mechanisms that modulate signalling may lead to the development of new therapies and may help to explain the mechanism of drug tolerance.